In general, the present invention relates to pregnancy-specific beta.sub.1 -glycoproteins. The present invention relates, in particular, to pregnancy-specific beta.sub.1 -glycoprotein mRNA that is preferentially expressed in human hydatidiform molar trophoblastic tissue.
Pregnancy-specific beta.sub.1 -glycoprotein (PS.beta.G) was the first of a group of pregnancy associated proteins identified (for reviews see Tatarinov, Y. S., 1978, Gynecol. Obstet. Invest. 9:65-97; and Sorensen, S., 1984, Tumor Biol. 5:275-302). It is detectable in maternal serum as early as 18 days after ovulation (Tatarinov, Y. S. and Masyukevich, V. N., 1970, Byull. Eksp. Biol. Med. USSR 69:66-68). Maternal serum concentrations reach 200-400 .mu.g/ml by the third trimester, making PS.beta.G a major secretory product of the human placenta (Tatarinov, Y. S. and Masyukevich, V. N., 1970, Byull. Eksp. Biol. Med. USSR 69:66-68; Lin, T. M., Halbert, S. P. and Spellacy, W. N., 1974, J. Clin. Invest. 54:576-582). PS.beta.G has been used clinically to diagnose pregnancy and to predict some pregnancy-related complications. For example, low PS.beta.G values are associated with poor pregnancy outcome in threatened abortions (Wurz, H., Geiger, W., Kunzig, H. J., Jabs-Lehmann, A., Bohn, H. and Luben, G., 1981, J. Perinat. Med. 2:67-78; Hertz, J. B. and Schultz-Larsen, P., 1983, Int. J. Gynaecol. Obstet. 21:111-117; Masson, G. M., Anthony, F. and Wilson, M. S., 1983, Br. J. Obstet. Gynaecol. 90:146-149), intrauterine growth retardation (Tamsen, L., Johansson, S. G. O. and Axelsson, O., 1983, J. Perinat. Med. 11:19-25), fetal hypoxia (MacDonald, D. J., Scott, J. M., Gemmel, R. S. and Mack, D. S., 1983, Am. J. Obstet. Gynecol. 147:430-436), and preeclampsia (Grudzinskas, J. G., Gordon, Y. B., Menabawey, M., Lee, J. N., Wadsworth, J. and Chard, T., 1983, Am. J. Obstet. Gynecol. 147:10-12). The clinical uses of PS.beta.G are not limited to pregnancy; it is found in the sera of most patients with hydatidiform mole, invasive mole, and choriocarcinoma (a treatable cancer with excellent prognosis) (Tatarinov, Y. S., 1978, Gynecol. Obstet. Invest. 9:65-97; Lin, T. M., Halbert, S. P. and Spellacy, W. N., 1974, J. Clin. Invest. 54:576-582), and it has been employed as a marker for monitoring the treatment of choriocarcinoma (Tatarinov, Y. S., 1978, Gynecol. Obstet. Invest. 9:65-97).
Although PS.beta.G has been used as a diagnostic marker, the present assays for PS.beta.G suffer from several shortcomings which limit their utility for such diagnostic purposes. First, the presently known PS.beta.G marker is a normal placental protein which is produced at variably high levels during pregnancy and thus is not specific for hydatidiform moles or choriocarcinomas, and elevated levels of this protein do not occur in the sera of all patients with these pathologic conditions. Thus there is a need for compositions and methods for more specific and reliable detection of human gestational trophoblastic diseases including hydatidiform moles and choriocarcinomas. The biological function of PS.beta.G is unknown. In order to more completely understand this potentially important protein and its function in pregnancy, the present inventor has undertaken a number of studies to characterize human PS.beta.G. Thus, it was found that placental PS.beta.G represents a family of closely related glycoproteins of 72, 64, and 54 kDa, and that placental poly(A).sup.+ RNA directed the synthesis of three polypeptides of 50, 48 (major), and 36 kDa as immunoprecipitated by anti-PS.beta.G serum (Watanabe, S. and Chou, J. Y., 1988, J. Biol. Chem. 263:2049-2054). Moreover, near-full length cDNAs encoding members of the PS.beta.G family were recently isolated and characterized in the laboratory of the present inventor (Watanabe, S. and Chou, J. Y., 1988, J. Biol. Chem. 263:2049-2054; Watanabe, S. and Chou, J. Y., 1988, in Placental and Endometrial Proteins, ed. Mizutani, S., VNU Science Press, Japan, pp. 155-158) as well as by others (Streydio, C., Lacka, K., Swillens, S. and Vassart, G., 1988, Biochem. Biophys. Res. Commun. 154:130-137; Rooney, B. C., Horne, C. H. W. and Hardman, N., 1988, Gene 71:439-449; Chan, W. Y., Borjigin, J., Zheng, Q.-X. and Shupert, W. L., 1988, DNA 7:545-555; Khan, W. N., Osterman, A. and Hammarstrom, S., 1989, Proc. Natl. Acad. Sci. U.S.A. 86:3332-3336; Khan, W. N. and Hammarstrom, S., 1989, Biochem. Biophys. Res. Commun. 161:525-535; McLenachan, T. and Mansfield, B., 1989, Biochem. Biophys. Res. Commun. 162:1486-1493; Zimmermann, W., Weiss, M. and Thompson, J. A., 1989, Biochem. Biophys. Res. Commun. 163:1197-1209; Niemann, S. C., Flake, A., Bohn, H. and Bartels, I., 1989, Hum. Genet. 82:239-243). Recently, two gene fragments which share strong sequence similarity with the reported PS.beta.G cDNAs have been reported (Oikawa, S., Inuzuka, C., Kosaki, G. and Nakazato, H., 1988, Biochem. Biophys. Res. Commun. 156:68-77; Oikawa, S., Inuzuka, C., Kuroki, M., Matsuoka, Y., Kosaki, G. and Nakazato, H., 1989, Biochem. Biophys. Res. Commun. 163:1021-1031).
A careful analysis of the structure of PS.beta.G has led to the discovery that it is closely related to the carcinoembryonic antigen (CEA) family (Oikawa, S., Nakazato, H. and Kosaki, G., 1987, Biochem. Biophys. Res. Commun. 142, 511-518; Beauchemin, N., Benchimol, S., Cournoyer, D., Furks, A. and Stanners, C. P., 1987, Mol. Cell Bio. 7, 3221-3230). CEA has recently been shown to be an intercellular adhesion molecule mediating aggregation of cultured human colon adenocarcinoma cells (Benchimol, S., Furks, A., Jothy, S., Beauchemin, N., Shirota, K. and Stanners, C. P., 1989, Cell 57, 327-334). Both PS.beta.G and CEA are members of the immunoglobulin superfamily (Streydio, C., Lacka, K., Swillens, S. and Vassart, G., 1988, Biochem. Biophys. Res. Commun. 154, 130-137; Rooney, B. C., Horne, C. H. W. and Hardman, N., 1988, Gene 71, 439-449; Chan, W.-Y., Borjigin, J., Zheng, Q.-X. and Shupert, W. L., 1988, DNA 7, 545-555; Oikawa, S., Nakazato, H., and Kosaki, G., 1987, Biochem. Biophys. Res. Commun. 142, 511-518; Beauchemin, N., Benchimol, S., Cournoyer, D., Furks, A. and Stanners, C. P., 1987, Mol. Cell Bio. 7, 3221-3230; Watanabe, S. and Chou, J. Y., 1988, Biochem. Biophys. Res. Commun. 152, 762-768) which includes proteins that are arranged in domains and have constant and variable regions. A group of proteins including neural cellular-adhesion molecule (N-CAM) (for a review see Cunningham, B. A., Hemperly, J. J., Murray, B. A., Predoger, E. A., Brackenbury, R. and Edelman, G. M., 1987, Science 236, 799-806) within the immunoglobulin superfamily contain the surface active tripeptide Arg-Gly-Asp which acts in cell-surface recognition. Many members of the PS.beta.G gene family (including PSGGB in this study) are closely related to N-CAM and encode proteins which contain the Arg-Gly-Asp tripeptide (Streydio, C., Lacka, K., Swillens, S. and Vassart, G., 1988, Biochem. Biophys. Res. Commun. 154, 130-137; Rooney, B. C., Horne, C. H. W. and Hardman, N., 1988, Gene 71, 439-449; Khan, W. N. and Hammarstrom, S., 1989, Biochem. Biophys. Res. Commun. 161, 525-535; Zimmermann, W., Weiss, M. and Thompson, J. A., 1989, Biochem. Biophys. Res. Commun. 163, 1197-1209; Oikawa, S., Inuzuka, C., Kuroki, M., Matsuoka, Y., Kosaki, G. and Nakazato, H., 1989, Biochem. Biophys. Res. Commun. 163 1021-1031). Further, the PSGGB-encoded protein may be involved in the genesis of gestational trophoblastic disease by acting as adhesion molecule. This hypothesis is supported by data demonstrating that PSGGB-like mRNA is preferentially expressed in molar trophoblastic tissue. The PSGGB-like product may also serve as a more specific marker for molar pregnancy.